The beta adrenergic receptors were classified as beta-1 and beta-2 by 1967. At the beginning of the '80s a new adrenergic receptor—subsequently called beta-3 adrenergic receptor—was discovered to be present in several species, including humans (Proc. Nutr. Soc. 1989, 48:215-223).
The beta-3 adrenergic receptor is expressed in various tissues among which are adipose tissue, heart, uterus, bladder and bowel, where it modulates different functions.
Agonist and antagonist compounds of the beta-3 adrenergic receptor have been synthesized and it has been observed that activation of the receptor by agonist compounds induces thermogenesis and increases sensitivity to insulin; in various animal models such effects cause a reduction of body weight and relieve the symptoms of diabetes.
It has been noticed that an increase in beta-3 adrenergic receptor function in visceral fat deposits can favor an increase in lipolysis and the consequent flux of portal non-esterified fatty-acids, thus causing harmful effects on liver metabolism. In fact, the non-esterified fatty acids stimulate secretion of VLDL (“very low density lipoproteins”) and gluconeogenesis and interfere with liver clearance of insulin causing dyslipoproteinemia, glucose intolerance and hyperinsulinemia, with effects on arterial blood pressure.
As stated, agonist and antagonist compounds have been reported, but until now no inverse agonists of the beta-3 adrenergic receptor have been described.